DESCRIPTION The objective of the proposed research is the enantioselective total synthesis of (-)-xestocyclamine A. This natural product belongs to the manzamine family of marine alkaloids and is a potent inhibitor of protein kinase C (PKC). Recent findings show that PKC plays an important role in cellular regulatory functions and is a possible target for cancer treatment. The initial goal of this research is the novel synthesis of a chiral 3-piperidinol containing a tetra-substituted olefin. This intermediate will play a vital role in the establishment of the core ring system stereochemistry and the incorporation of macrocycle precursors. An intramolecular alkyne-azadiene Diels-Alder reactions will simultaneously form three rings, which include a macrocycle and a complex [2,2,2] bridged bicyclic systems. The face- and regioselectivity of the Diels-Alder reaction can be controlled by the tether length of the dienophile and the conformation of the azadiene. The regio-chemistry may also be influenced by electron donating alkynyl auxiliaries, which are easily incorporated into the synthesis. The final macrocycle of xestocyclamine A will be formed by a ring-closing olefin metathesis reaction. The xestocyclamine A will be formed by a ring-closing olefin metathesis reaction. The development of this convergent synthesis of xestocyclamine A will ultimately lead to the synthesis of analogs to probe the biological activities of this alkaloid.